新型温度敏感性双亲性嵌段共聚物的设计、合成、自组装行为及其在生物医学上应用的研究

发布时间：2018-04-29 12:03

本文选题：双亲性嵌段共聚物 + 温度敏感性　；参考：《兰州大学》2017年硕士论文

【摘要】：两亲性嵌段共聚物同时含有亲水和疏水链段,其自组装形成的胶束,因独特的核-壳结构在纳米药物领域作为药物传递系统引起了人们的广泛关注。透析法是制备基于两亲性嵌段共聚物自组装胶束的最常用方法,然而透析法一方面需要使用有机溶剂,另一方面耗时,因此限制了其实际和在临床上的应用。双亲性嵌段共聚物不同于两亲性嵌段共聚物,其两段都是亲水的,因此在水溶液中是完全可溶的,如果双亲性嵌段共聚物其中一段是温度敏感性聚合物链段,则可以通过在水相中单纯改变环境温度完成聚合物的自组装,因此与两亲性嵌段共聚物通过透析的方法完成自组装相比,是一种更为绿色和快捷的方法。在本学位论文中,我们一方面通过首次设计和制备牙刷形双亲性嵌段共聚物,研究了聚合物的拓扑结构对其自组装行为的影响,另一方面我们将双亲性嵌段共聚物应用于设计和制备聚合物前药,通过比较研究阐明了药物分子的键合位点对聚合物前药性能的影响。具体研究内容及结果如下:1.通过连续两步RAFT反应制备了基于分子量为300的寡聚聚乙二醇单体和异丙基丙烯酰胺单体的牙刷形双亲性嵌段共聚物P(NIPAAm)-b-P(OEGMA300),通过UV-vis以及DLS考察了该双亲性嵌段共聚物的水溶液在不同温度下的相转变和组装行为,通过TEM和SEM观察了其组装体的形貌。同时还合成了P(NIPAAm)-b-P(HPMA)和P(NIPAAm)-b-P(OEGMA480)作为对照组,对比研究了其相转变和组装行为,以及形貌变化。研究发现,侧链悬挂的OEG刷与PNIPAAm的链缠结作用使得P(NIPAAm)133-b-P(OEGMA300)17在由25度升温至45度的过程中,具有从单聚体-囊泡、囊泡-胶束的两阶段转变。远端自由的PNIPAAm在升温过程中的链收缩主导单聚体-囊泡的转变,而近端受限的PNIPAAm的链段收缩主导囊泡-胶束的转变过程。由温度引起的两阶段的相转变行为也适用于基于分子量为480的寡聚聚乙二醇单体(OEGMA480)的牙刷形双亲性嵌段共聚物P(NIPAAm)-b-P(OEGMA480)。2.通过连续RAFT聚合以及聚合后修饰的方法将抗癌药物阿霉素(DOX)通过pH响应的腙键分别键合在双亲性嵌段共聚物的亲水链段和温度敏感链段,制备得到了两种组成相近但药物键合位点不同的双亲性聚合物前药P(HPMA)-b-P(NIPAAm-st-(EGMA-DOX))和P(HPMA-st-(EGMA-DOX))-b-P(NIPAAm)。通过DLS测量两种聚合物前药溶液在升温条件下的粒径变化,发现在人体正常生理温度,两种聚合物前药胶束具有相似的粒径且均表现出较好的稳定性。分别在人体正常生理pH值(7.4),肿瘤弱酸性环境(pH 6.8)和细胞内内涵体和溶酶体的酸性条件下(pH 5.0),考察了两种聚合物前药的体外药物释放行为,发现将药物键合在胶束的亲水外壳可以显著促进药物从胶束中释放。采用MTT法考察了两种聚合物前药胶束在A549和MDA-MB-435细胞系中的体外细胞毒性,结果说明将药物键合在胶束的亲水外壳表现出更高的体外细胞毒性。
[Abstract]:Amphiphilic block copolymers contain both hydrophilic and hydrophobic chains. Their self-assembled micelles have attracted much attention due to their unique core-shell structure as drug delivery systems in the field of nanopharmaceuticals. Dialysis is the most common method for preparing self-assembled micelles based on amphiphilic block copolymers. However, dialysis requires organic solvents on the one hand, and time-consuming on the other, which limits its practical and clinical application. Amphiphilic block copolymers are different from amphiphilic block copolymers in that they are hydrophilic and therefore completely soluble in aqueous solution, if one of the amphiphilic block copolymers is a thermo-sensitive polymer chain, The self-assembly of polymers can be completed by simply changing the ambient temperature in aqueous phase, so it is a greener and faster method than that of amphiphilic block copolymers by dialysis. In this dissertation, we first designed and prepared toothbrush amphiphilic block copolymers to study the effect of polymer topology on self-assembly behavior. On the other hand, we used amphiphilic block copolymers to design and prepare polymer prodrugs. The specific research contents and results are as follows: 1. The toothbrush amphiphilic block copolymers PniPAAmam-b-Pao OEGMA300 based on oligomeric poly (ethylene glycol) and isopropyl acrylamide monomer were prepared by continuous two-step RAFT reaction. The amphiphilic block copolymers were investigated by UV-vis and DLS. Phase transition and Assembly behavior of Aqueous solution at different temperatures, The morphology of the assembly was observed by TEM and SEM. The phase transition, assembly behavior and morphologic changes of PNIPAAm-b-PGMA480 and PNIPAAm-b-PGMA480 were also synthesized as control group. It is found that the chain entanglement between the side chain suspension OEG brush and the PNIPAAm leads to the two-stage transition of P(NIPAAm)133-b-P(OEGMA300)17 from monomeric vesicles to micelles in the process of rising from 25 to 45 degrees. The chain contraction of distal free PNIPAAm dominates the transition of monomaterials to vesicles, while the segment contraction of PNIPAAm at the proximal end dominates the transition of vesicles to micelles. The two-stage phase transition behavior induced by temperature can also be applied to the toothbrush amphiphilic block copolymers PniPAAm-b-POEGMA480.2based on oligopolyethylene glycol monomer OEGMA480 (molecular weight 480). The anticancer drug adriamycin dox was bonded to the hydrophilic and temperature-sensitive segments of the amphiphilic block copolymer via pH responsive Hydrazone bond by continuous RAFT polymerization and post-polymerization modification. Two amphiphilic polymer prodrugs, PnHPMA-b-PNPAAm-st-EGMA-DOXA) and PHPMA-st-UEGMA-DOXN, were prepared, and two amphiphilic polymer prodrugs, PHPMA-st-ng-EGMA-DOX- b-PNIPAAman, with similar composition but different drug binding sites, were prepared. The particle size changes of two kinds of polymer prodrug solution were measured by DLS. It was found that the two polymer prodrug micelles had similar particle size and showed good stability at normal physiological temperature of human body. The release behavior of two kinds of polymer prodrugs in vitro were investigated under normal physiological pH value of 7.4 and pH 6.8 of tumor weak acidic environment and pH 5.0 of intracellular connoisomes and lysosomes, respectively. It is found that the drug binding to the hydrophilic shell of the micelle can significantly promote the release of the drug from the micelle. The in vitro cytotoxicity of two kinds of polymer prodrug micelles in A549 and MDA-MB-435 cell lines was investigated by MTT method. The results showed that the drug binding in the hydrophilic shell of the micelles showed higher cytotoxicity in vitro.
【学位授予单位】：兰州大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：O631;TQ460.1

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